| 1 | Schizophr. Res. 2010 Jun 119: 198-209 |
|---|---|
| PMID | 20347576 |
| Title | Expression of the NR2B-NMDA receptor trafficking complex in prefrontal cortex from a group of elderly patients with schizophrenia. |
| Abstract | Dysregulated glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. In particular, hypofunction of the NMDA glutamate receptor has been proposed to play an important role in mediating cognitive deficits in patients. The two NMDA receptor subunits, NR2A and NR2B, are distinctly regulated during development and are associated with different intracellular pathways and functions, which suggest that these receptors play separate roles in the control of higher cognitive functions such as learning and memory. Trafficking of the NR2B subunit-containing receptor is regulated by a microtubule-associated trafficking complex consisting of the KIF17, APBA1, CASK, and mLin7 proteins. Several studies have demonstrated an integrated functional regulation of this trafficking complex with NR2B receptor subunit expression, which in turn has been linked to higher cognitive functions. In the present work, we investigated whether expression of this NR2B-associated trafficking complex might be abnormal in schizophrenia. We analyzed the expression of KIF17, APBA1, CASK, mLin7A and mLin7C in postmortem brain from patients with schizophrenia a comparison group. Analysis of transcripts for all of these proteins revealed particularly prominent expression in cortical layer III and layer IV, which overlapped with NR2B but not NR2A transcripts. We found altered expression of transcripts for the CASK, ABPA1, and mLin7 molecules and the CASK, mLin7 proteins, suggesting that NR2B-containing NMDA receptor transport could be selectively compromised in schizophrenia, and that these changes likely involve altered NR2B function in a subset of cortical neurons. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Biol. Psychiatry 2010 Oct 68: 649-56 |
| PMID | 20646681 |
| Title | De novo truncating mutation in Kinesin 17 associated with schizophrenia. |
| Abstract | schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ. As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish. Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect. Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J. Neurosci. 2015 Jun 35: 8986-96 |
| PMID | 26085624 |
| Title | ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization. |
| Abstract | NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca(2+)/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Mol. Genet. Genomics 2015 Apr 290: 585-92 |
| PMID | 25354644 |
| Title | Common variants of the PINK1 and PARL genes do not confer genetic susceptibility to schizophrenia in Han Chinese. |
| Abstract | schizophrenia is a prevalent psychiatric disorder with a complex etiology. Mitochondrial dysfunction has been frequently reported in schizophrenia. Phosphatase and tension homologue-induced kinase 1 (PINK1) and presenilin-associated rhomboid-like protease (PARL) are mitochondrial proteins, and genetic variants of these two genes may confer genetic susceptibility to schizophrenia by influencing mitochondrial function. In this study, we conducted a two-stage genetic association study to test this hypothesis. We genotyped 4 PINK1 and 5 PARL genetic variants and evaluated the potential association of the 9 SNPs with schizophrenia in two independent case-control cohorts of 2510 Han Chinese individuals. No positive association of common genetic variants of the PINK1 and PARL genes with schizophrenia was identified in our samples after Bonferroni correction. Re-analysis of the newly updated Psychiatric Genetics Consortium (PGC) data sets confirmed our negative result. Intriguingly, one PINK1 SNP (rs10916832), which showed a marginally significant association in only Hunan samples (P = 0.032), is associated with the expression of a schizophrenia susceptible gene KIF17 according to the expression quantitative trait locus (eQTL) analysis. Our study indicated that common genetic variants of the PINK1 and PARL genes are unlikely to be involved in schizophrenia. Further studies are essential to characterize the role of the PINK1 and PARL genes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Psychiatry Res 2015 Dec 230: 424-9 |
| PMID | 26421900 |
| Title | A decrease in protein level and a missense polymorphism of KIF17 are associated with schizophrenia. |
| Abstract | It has been shown that the dysfunction of N-methyl-d-asparate (NMDA) receptors-mediated neurotransmission plays a role in the pathophysiology of schizophrenia. Especially, GluN2B, a subunit of NMDA receptors, associated trafficking complex is altered in the prefrontal cortex of schizophrenia. The kinesin superfamily motor protein 17 (KIF17) is known as a transporter of NR2B.Previous studies showed that a structural variant of KIF17 gene is associated with a schizophrenic phenotype. Therefore, here we investigated KIF17 levels in postmortem prefrontal cortex in schizophrenia and the association of a missense polymorphism (Ile341Val) in KIF17 with schizophrenia. The protein expression of KIF17 in schizophrenic postmortem brains was significantly lower than that in controls. Next, the association of missense polymorphisms (rs631375, rs13375609, rs522496 and rs2296225) of KIF17 gene in 567 schizophrenia and 710 healthy subjects was examined. Both genotypic distribution and allelic frequency of rs2296225 polymorphism were significantly different between the chronic schizophrenia subjects and controls. However, our findings described above were not replicated with the independent subjects (555 schizophrenia and 814 healthy controls). Furthermore, the two alleles of rs2296225 polymorphism did not affect the mRNA expression of KIF17. These results suggest that the dysfunction of KIF17 might be involved in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Psychiatry Res 2015 Dec 230: 424-9 |
| PMID | 26421900 |
| Title | A decrease in protein level and a missense polymorphism of KIF17 are associated with schizophrenia. |
| Abstract | It has been shown that the dysfunction of N-methyl-d-asparate (NMDA) receptors-mediated neurotransmission plays a role in the pathophysiology of schizophrenia. Especially, GluN2B, a subunit of NMDA receptors, associated trafficking complex is altered in the prefrontal cortex of schizophrenia. The kinesin superfamily motor protein 17 (KIF17) is known as a transporter of NR2B.Previous studies showed that a structural variant of KIF17 gene is associated with a schizophrenic phenotype. Therefore, here we investigated KIF17 levels in postmortem prefrontal cortex in schizophrenia and the association of a missense polymorphism (Ile341Val) in KIF17 with schizophrenia. The protein expression of KIF17 in schizophrenic postmortem brains was significantly lower than that in controls. Next, the association of missense polymorphisms (rs631375, rs13375609, rs522496 and rs2296225) of KIF17 gene in 567 schizophrenia and 710 healthy subjects was examined. Both genotypic distribution and allelic frequency of rs2296225 polymorphism were significantly different between the chronic schizophrenia subjects and controls. However, our findings described above were not replicated with the independent subjects (555 schizophrenia and 814 healthy controls). Furthermore, the two alleles of rs2296225 polymorphism did not affect the mRNA expression of KIF17. These results suggest that the dysfunction of KIF17 might be involved in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |